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The impact of delayed treatment of uncomplicated P. falciparum malaria on progression to severe malaria: a systematic review and a pooled multicentre individual-patient meta-analysis

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Title: The impact of delayed treatment of uncomplicated P. falciparum malaria on progression to severe malaria: a systematic review and a pooled multicentre individual-patient meta-analysis
Authors: Mousa, A
Al-Taiar, A
Anstey, NM
Badaut, C
Barber, BE
Bassat, Q
Challenger, J
Cunnington, AJ
Datta, D
Drakeley, C
Ghani, AC
Gordeuk, VR
Grigg, MJ
Hugo, P
John, CC
Mayor, A
Migot-Nabias, F
Opoka, RO
Pasvol, G
Rees, C
Reyburn, H
Riley, EM
Shah, BN
Sitoe, A
Sutherland, CJ
Thuma, PE
Unger, SA
Viwami, F
Walther, M
Whitty, CJM
William, T
Okell, LC
Item Type: Journal Article
Abstract: Background: Delay in receiving treatment for uncomplicated malaria is often reported to increase the risk of developing severe malaria, but access to treatment remains low in most high-burden areas. Understanding the contribution of treatment delay on progression to severe disease is critical to determine how quickly patients need to receive treatment and to quantify the impact of widely implemented treatment interventions, such as “test-and-treat” policies administered by community health workers. We conducted a pooled individual-participant meta-analysis to estimate the association between treatment delay and presenting with severe malaria.Methods and Findings: A search using Ovid MEDLINE and Embase was initially conducted to identify studies on severe P. falciparum malaria which included information on treatment delay, such as fever duration 12(inceptions to 22nd September 2017). Studies identified included five case-control and eight other observational clinical studies of severe and uncomplicated malaria cases. Risk of bias was assessed using the Newcastle–Ottawa scale and all studies were ranked as “Good”, scoring ≥7/10. Individual-patient data were pooled from thirteen studies of 3,989(94.1% aged <15 years)severe malaria patients and 5,780(79.6% aged <15 years)uncomplicated malaria cases in Benin, Malaysia, Mozambique, Tanzania, The Gambia, Uganda, Yemen and Zambia. Definitions of severe malaria were standardised across studies to compare treatment delay in patients with uncomplicated malaria and different severe malaria phenotypes using age-adjusted mixed-effects regression. The odds of any severe malaria phenotype were significantly higher in children with longer delays between initial symptoms and arrival at the health facility (OR=1.33, 95%CI:1.07-1.64 for a delay of >24 hours vs. ≤24 hours;p=0.009). Reported illness duration was a strong predictor of presenting with severe malarial anaemia (SMA) in children, with an OR of 2.79 (95%CI:1.92-4.06;p<0.001) for a delay of 2-3 days and 5.46 (95%CI:3.49-8.53; p<0.001) for a delay of >7 days, compared to receiving treatment within 24 hours from symptom onset. We estimate that 42.8% of childhood SMA cases and 48.5%of adult SMA cases in the study areas would have been averted if all individuals were able to access treatment within the first day of symptom onset, if the association is fully causal. In studies specifically recording onset of non-severe symptoms, long treatment delay was moderately associated with other severe malaria phenotypes [OR(95%CI)>3 to≤4 days vs. ≤24 hours: Cerebral Malaria=2.42(1.24-4.72), p=0.01; Respiratory Distress=4.09(1.70-9.82), p=0.002]. In addition to unmeasured confounding, commonly present in observational studies, a key limitation is that many severe cases and deaths occur outside healthcare facilities in endemic countries, where the effect of delayed or no treatment is difficult to quantify. Conclusions: Our results quantify the relationship between rapid access to treatment and reduced risk of severe disease, which was particularly strong for SMA. There was some evidence to suggest that progression to other severe phenotypes may also be prevented by prompt treatment, though the association was not as strong, which may be explained by potential selection bias, sample size issues or a difference in underlying pathology. These findings may help assess the impact of interventions which improve access to treatment.
Issue Date: 19-Oct-2020
Date of Acceptance: 26-Aug-2020
URI: http://hdl.handle.net/10044/1/82725
DOI: 10.1371/journal.pmed.1003359
ISSN: 1549-1277
Publisher: Public Library of Science (PLoS)
Start Page: 1
End Page: 28
Journal / Book Title: PLoS Medicine
Volume: 17
Issue: 10
Copyright Statement: © 2020 Mousa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Sponsor/Funder: The Royal Society
Medical Research Council (MRC)
Medical Research Council (MRC)
Funder's Grant Number: DH140134
MR/R015600/1
MR/L006529/1
Keywords: 11 Medical and Health Sciences
General & Internal Medicine
Publication Status: Published
Online Publication Date: 2020-10-19
Appears in Collections:Department of Infectious Diseases
Faculty of Medicine
School of Public Health



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